FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

  • Nature. 2022 Dec 5. doi: 10.1038/s41586-022-05594-0.
Teresa Brevini  1 ,  Mailis Maes  2 ,  Gwilym J Webb  3 ,  Binu V John  4 ,  Claudia D Fuchs  5 ,  Gustav Buescher  6 ,  Lu Wang  7 ,  Chelsea Griffiths  7 ,  Marnie L Brown  7 ,  William E Scott 3rd  7 ,  Pehuén Pereyra-Gerber  2 ,  William T H Gelson  3  8 ,  Stephanie Brown  9 ,  Scott Dillon  9 ,  Daniele Muraro  10 ,  Jo Sharp  11 ,  Megan Neary  11 ,  Helen Box  11 ,  Lee Tatham  11 ,  James Stewart  12 ,  Paul Curley  11 ,  Henry Pertinez  11 ,  Sally Forrest  2 ,  Petra Mlcochova  2  4 ,  Sagar S Varankar  9 ,  Mahnaz Darvish-Damavandi  9  13 ,  Victoria L Mulcahy  14 ,  Rhoda E Kuc  15 ,  Thomas L Williams  15 ,  James A Heslop  9 ,  Davide Rossetti  9 ,  Olivia C Tysoe  9  16 ,  Vasileios Galanakis  9 ,  Marta Vila-Gonzalez  9 ,  Thomas W M Crozier  2 ,  Johannes Bargehr  9  8  17 ,  Sanjay Sinha  9  17 ,  Sara S Upponi  18 ,  Corrina Fear  16 ,  Lisa Swift  16 ,  Kourosh Saeb-Parsy  16  19 ,  Susan E Davies  20 ,  Axel Wester  21 ,  Hannes Hagström  21 ,  Espen Melum  22  23  24  25  26 ,  Darran Clements  9 ,  Peter Humphreys  9 ,  Jo Herriott  11 ,  Edyta Kijak  11 ,  Helen Cox  11 ,  Chloe Bramwell  11 ,  Anthony Valentijn  11 ,  Christopher J R Illingworth  27  28 ,  UK-PBC research consortium ,  Bassam Dahman  29 ,  Dustin R Bastaich  29 ,  Raphaella D Ferreira  4 ,  Thomas Marjot  30 ,  Eleanor Barnes  30 ,  Andrew M Moon  31 ,  Alfred S Barritt 4th  31 ,  Ravindra K Gupta  2  8 ,  Stephen Baker  2 ,  Anthony P Davenport  15 ,  Gareth Corbett  32 ,  Vassilis G Gorgoulis  33  34  35 ,  Simon J A Buczacki  9  13 ,  Joo-Hyeon Lee  9  36 ,  Nicholas J Matheson  2  8  31  37 ,  Michael Trauner  5 ,  Andrew J Fisher  7 ,  Paul Gibbs  16  19 ,  Andrew J Butler  16  19 ,  Christopher J E Watson  16  19  38 ,  George F Mells  3  14 ,  Gordon Dougan  2 ,  Andrew Owen  11 ,  Ansgar W Lohse  6 ,  Ludovic Vallier  39  40  41  42 ,  Fotios Sampaziotis  43  44  45
Affiliations
  • 1. Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK. [email protected].
  • 2. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
  • 3. Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 4. Division of Gastroenterology and Hepatology, University of Miami and Miami VA Health System, Miami, FL, USA.
  • 5. Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
  • 6. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
  • 7. Transplant and Regenerative Medicine Laboratory, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
  • 8. Department of Medicine, University of Cambridge, Cambridge, UK.
  • 9. Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • 10. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  • 11. Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
  • 12. Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
  • 13. Nuffield Department of Surgical Sciences, Old Road Campus Research Building, Oxford, UK.
  • 14. Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
  • 15. Experimental Medicine and Immunotherapeutics, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
  • 16. Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research centre, Cambridge, UK.
  • 17. Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
  • 18. Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 19. Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 20. Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 21. Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
  • 22. Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
  • 23. Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
  • 24. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
  • 25. Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
  • 26. Hybrid Technology Hub Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
  • 27. MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
  • 28. Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK.
  • 29. Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, VA, USA.
  • 30. Oxford Liver Unit, Translational Gastroenterology Unit, Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxford, UK.
  • 31. Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA.
  • 32. Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 33. Dept. of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
  • 34. Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
  • 35. Biomedical Research Foundation, Academy of Athens, Athens, Greece.
  • 36. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • 37. NHS Blood and Transplant, Cambridge, UK.
  • 38. National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre, and the NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), Cambridge, UK.
  • 39. Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK. [email protected].
  • 40. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. [email protected].
  • 41. Berlin Institute of Health (BIH), BIH Centre for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany. [email protected].
  • 42. Max Planck Institute for Molecular Genetics, Berlin, Germany. [email protected].
  • 43. Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK. [email protected].
  • 44. Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. [email protected].
  • 45. Department of Medicine, University of Cambridge, Cambridge, UK. [email protected].
PMID: 36470304 DOI: 10.1038/s41586-022-05594-0
Abstract

Prevention of SARS-CoV-2 Infection through the modulation of viral host receptors, such as ACE21, could represent a new chemoprophylactic approach for COVID-19 complementing vaccination2,3. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We demonstrate that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV-2 Infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 Infection using retrospective registry data, and confirm these findings in an independent validation cohort of liver transplant recipients. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 Infection, paving the road for future clinical trials.

Products